Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Blood proteins or globulins – e.g. – proteoglycans – platelet...
Reexamination Certificate
1998-10-14
2001-12-04
Spector, Lorraine (Department: 1646)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Blood proteins or globulins, e.g., proteoglycans, platelet...
C530S388850, C424S185100, C514S002600, C536S023500
Reexamination Certificate
active
06326472
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to compositions and methods for affecting mammalian physiology, including, e.g., morphogenesis or immune system function. In particular, it provides nucleic acids, proteins, and antibodies, e.g., which regulate development and/or the immune system along with related reagents and methods. Diagnostic and therapeutic uses of these materials are also disclosed.
BACKGROUND OF THE INVENTION
Recombinant DNA technology refers generally to techniques of integrating genetic information from a donor source into vectors for subsequent processing, such as through introduction into a host, whereby the transferred genetic information is copied and/or expressed in the new environment. Commonly, the genetic information exists in the form of complementary DNA (cDNA) derived from messenger RNA (mRNA) coding for a desired polypeptide product. The carrier is frequently a plasmid having the capacity to incorporate cDNA for later replication and/or expression in a host and, in some cases, actually to control expression of the cDNA and thereby direct synthesis of the encoded product in the host.
For some time, it has been known that the mammalian immune response is based on a series of complex cellular interactions, called the “immune network”. Recent research has provided new insights into the inner workings of this network. While it remains clear that much of the immune response does, in fact, revolve around the network-like interactions of lymphocytes, macrophages, granulocytes, and other cells, immunologists now generally hold the opinion that soluble proteins, known as lymphokines, cytokines, or monokines, play critical roles in controlling these cellular interactions. Thus, there is considerable interest in the isolation, characterization, and mechanisms of action of cell modulatory factors, an understanding of which will lead to significant advancements in the diagnosis and therapy of numerous medical abnormalities, e.g., immune system disorders.
Lymphokines apparently mediate cellular activities in a variety of ways. They have been shown to support the proliferation, growth, and/or differentiation of pluripotential hematopoietic stem cells into vast numbers of progenitors comprising diverse cellular lineages which make up a complex immune system. Proper and balanced interactions between the cellular components are necessary for a healthy immune response. The different cellular lineages often respond in a different manner when lymphokines are administered in conjunction with other agents.
Cell lineages especially important to the immune response include two classes of lymphocytes: B-cells, which can produce and secrete immunoglobulins (proteins with the capability of recognizing and binding to foreign matter to effect its removal), and T-cells of various subsets that secrete lymphokines and induce or suppress the B-cells and various other cells (including other T-cells) making up the immune network. These lymphocytes interact with many other cell types.
Another important cell lineage is the mast cell (which has not been positively identified in all mammalian species), which is a granule-containing connective tissue cell located proximal to capillaries throughout the body. These cells are found in especially high concentrations in the lungs, skin, and gastrointestinal and genitourinary tracts. Mast cells play a central role in allergy-related disorders, particularly anaphylaxis as follows: when selected antigens crosslink one class of immunoglobulins bound to receptors on the mast cell surface, the mast cell degranulates and releases mediators, e.g., histamine, serotonin, heparin, and prostaglandins, which cause allergic reactions, e.g., anaphylaxis.
Research to better understand and treat various immune disorders has been hampered by the general inability to maintain cells of the immune system in vitro. Immunologists have discovered that culturing many of these cells can be accomplished through the use of T-cell and other cell supernatants, which contain various growth factors, including many of the lymphokines.
The interleukin-1 family of proteins includes the IL-
1
&agr;, the IL-1&bgr;, the IL-1RA, and recently the IL-1&ggr; (also designated Interferon-Gamma Inducing Factor, IGIF). This related family of genes has been implicated in a broad range of biological functions. See Dinarello (1994)
FASEB J.
8:1314-1325; Dinarello (1991)
Blood
77:1627-1652; and Okamura, et al. (1995)
Nature
378:88-91.
From the foregoing, it is evident that the discovery and development of new soluble proteins and their receptors, including ones similar to lymphokines, should contribute to new therapies. A number of degenerative or abnormal conditions directly or indirectly involve development, differentiation, or function, e.g., of the immune system and/or hematopoietic cells. In particular, the discovery and understanding of novel receptors for lymphokine-like molecules which enhance or potentiate the beneficial activities of other lymphokines, would be highly advantageous. The present invention provides new receptors for ligands exhibiting similarity to interleukin-1 like compositions and related compounds, and methods for their use.
SUMMARY OF THE INVENTION
The present invention is directed to novel receptors related to IL-1 receptors and their biological activities. These receptors, e.g., primate or rodent, are designated IL-1 receptor like molecular structures, IL-1 Receptor DNAX designation 8 (IL-1RD8), IL-1 Receptor DNAX designation 9 (IL-1RD9) and IL-1 Receptor DNAX designation 10 (IL-1RD10). The invention includes nucleic acids coding for the polypeptides themselves and methods for their production and use. The nucleic acids of the invention are characterized, in part, by their homology to cloned complementary DNA (cDNA) sequences enclosed herein.
In certain embodiments, the invention provides a composition of matter selected from the group of: an isolated or recombinant IL-1RD8 polypeptide comprising a segment of at least 12 contiguous amino acids of SEQ ID NO: 2 or 4, a natural sequence IL-1RD8 polypeptide comprising SEQ ID NO: 2 or 4, a fusion protein comprising IL-1RD8 sequence; an isolated or recombinant IL-1RD9 polypeptide comprising at least 12 contiguous amino acids of SEQ ID NO: 6, 8, 10, 12, 14, or 16; a natural sequence IL-1RD9 comprising SEQ ID NO: 6, 8, 10, 12, 14, or 16; a fusion protein comprising IL-1RD9 sequence; an isolated or recombinant IL-1RD10 polypeptide comprising at least 12 contiguous amino acids of SEQ ID NO: 18, 20, or 35; a natural sequence IL-1RD10 comprising SEQ ID NO: 18, 20, or 35; and a fusion protein comprising IL-1RD10 sequence. In various embodiments, the recombinant or isolated polypeptide comprises a segment identical to a corresponding portion of an IL-1RD8, as described, wherein: the number of contiguous amino acid residues is: at least 17 amino acids; at least 21 amino acids; or at least 25 amino acids; or to a corresponding portion of an IL-1RD9, as described, wherein the number of identical contiguous amino acid residues is: at least 17 amino acids; at least 21 amino acids; or at least 25 amino acids; or of an IL-1RD10, as described, wherein the number of identical contiguous amino acid residues is: at least 17 amino acids; at least 21 amino acids; or at least 25 amino acids.
In polypeptide embodiments, the invention provides a composition of matter wherein the IL-1RD8 comprises a mature sequence of Table 1; an IL-1RD9 that comprises a mature sequence of Table 2; an IL-1RD10 that comprises a mature sequence of Table 3; or the IL-1RD8, IL-1RD9, or IL-1RD10 polypeptide: is from a warm blooded animal, e.g., a primate, such as a human; comprises at least one polypeptide segment of SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, or 35; exhibits a plurality of portions having segments identical to specific sequence identifiers; is a natural allelic variant of a primate IL-1RD8; a primate or rodent IL-1RD9; or a primate IL-1RD10; has a length at least about 30 amino acids; exhibits at least two non-overlapping ep
Bazan J. Fernando
Debets Johannes Eduard Maria Antonius
Kastelein Robert A.
Sana Theodore R.
Timans Jacqueline C.
Ching Edwin P.
Mohan-Peterson Sheela
O'Hara Eileen B.
Schering Corporation
Spector Lorraine
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